tbuckley/cabot-search huggingface dataset:
NIMG-43. DIFFUSION BASIS SPECTRUM IMAGING DISTINGUISHES HIGH-GRADE GLIOMA TREATMENT EFFECT FROM TUMOR PROGRESSION
Authors: Rowland Han, Tanner Johanns, Jacob Blum, Zezhong Ye, Peng Sun, Tsen-Hsuan Lin, Albert Kim, Sheng-Kwei Song
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Following standard-of-care chemoradiation therapy for high-grade glioma, it is often challenging to distinguish treatment changes from true tumor progression using conventional magnetic resonance imaging (MRI). Diffusion basis spectrum imaging (DBSI) uses a data-driven multiple-tensor modeling approach to disentangle specific histologic components and structural features present within individual imaging voxels, offering an opportunity to noninvasively differentiate treatment effect from tumor progression. This represents the first study of in vivo longitudinal DBSI for brain tumors in patients. METHODS Adult patients were prospectively recruited who met the criteria of known pathological diagnosis of high-grade glioma or glioblastoma (WHO grade III-IV) and undergoing or completing standard-of-care radiation therapy with concurrent chemotherapy. DBSI and conventional MRI data were acquired longitudinally beginning with a 4-week post-radiation therapy MRI until progression as defined by standard RANO criteria or biopsy. DBSI analyses were performed with isotropic diffusion profiles defined as restricted fraction (0 ≤ D ≤ 1.0 μm2/ms) and hindered fraction (1.0 &amp;lt; D ≤ 1.5 μm2/ms). RESULTS Eleven patients with contrast-enhancing high-grade gliomas were enrolled between June 2019 and March 2020, with final DBSI data obtained in November 2020. Of these, eight patients had tumor progression, two had treatment effect, and one had stable disease during the study period. Within the contrast-enhancing regions, the DBSI hindered fraction map demonstrated hypointensity for all cases of tumor progression, and hyperintensity for cases of treatment effect. DBSI-based biomarkers were present 0.7 to 12.0 months (median 2.4, IQR 2.8) before definitive diagnosis of treatment effect or tumor progression using conventional methods of MRI and/or biopsy. CONCLUSIONS DBSI hindered fraction can distinguish new contrast-enhancing lesions in the setting of high-grade glioma as treatment effect or tumor progression in advance of conventional MRI. Future work will incorporate machine learning algorithms to further improve DBSI-based predictions of tumor histopathology.
NCOG-04. RANO-BM RESPONSE CRITERIA VERIFICATION STUDY IN A SRS-TREATED COHORT
Authors: Keiss Douri, Christian Iorio-Morin, Rosalie Mercure-Cyr, Gabrielle Figueiredo, Charles Touchette, Laurence Masson-Côté, David Mathieu
Journal: Neuro-Oncology (2022)

Abstract Brain metastases are frequently seen in neurosurgical practice. Standardised criteria are created to better classify these common pathologies in research studies. This study’s goal was to evaluate RANO-BM (Response Assessment in Neuro-Oncology - Brain Metastases) criteria’s current thresholds in a cohort of patients with brain metastases managed by stereotactic radiosurgery (SRS). We performed a retrospective metastasis-level analysis of patients treated with SRS for brain metastases. The data collected included cohort demographics, metastases characteristics, outcomes, and the rate of true positives, false negatives, true negatives and false positives as defined by RANO-BM criteria at last follow-up before second SRS. 251 metastases in 50 patients were included in the analysis. RANO-BM criteria using current thresholds yielded a sensitivity of 38%, a specificity of 95%, a positive predictive value of 71% and a negative predictive value of 84%. Modified RANO-BM criteria using absolute diameter differences of 2.5 mm yielded a sensitivity of 83%, a specificity of 87%, a positive predictive value of 67% and a negative predictive value of 94%. Pseudoprogression occurred significantly earlier than tumor progression, with a median time of onset of 6.9 months and 12.1 months respectively. Current RANO-BM criteria unreliably identifies clinically relevant tumor progression, but are useful in assessing diameter increases caused by tumor progression and pseudoprogression.
EXTH-45. TARGETING GLIOBLASTOMA BY NOVEL INTEGRIN-SPECIFIC CAR T CELLS
Authors: Danielle Villars, Lena Haensch, Manuela Silginer, Tobias Weiss, Michael Weller, Patrick Roth
Journal: Neuro-Oncology (2022)

Abstract RATIONALE Innovative treatment strategies are urgently needed to improve the prognosis of glioblastoma patients. Chimeric antigen receptor (CAR) T cell therapy has shown great success in hematological malignancies. However, it remains to be shown that CAR T cells are also active against solid tumors. αv integrins are overexpressed in gliomas and have already been used as therapeutic targets for small molecule inhibitors and antibodies. While these approaches were well tolerated, they did not exert meaningful clinical activity in glioblastoma patients. We aimed at exploiting the presence of αv integrins as targets for anti-glioma CAR T cell therapy. METHODS CAR T cells targeting specific integrin heterodimers (αvβ3, αvβ5 or αvβ8) were generated and their anti-glioma activity was determined in co-culture assays with different glioma cells. The efficacy of CAR T cells to control tumor growth in vivo was assessed in clinically relevant orthotopic mouse glioma models. RESULTS All newly generated integrin-targeting CAR T cells exerted strong anti-tumor activity in vitro. The highest lytic activity against glioma cells was observed for αvβ5 and αvβ8 integrin-specific CAR T cells. CAR T cells generated from patient-derived immune cells displayed strong lytic activity when tested against autologous tumors cells. Glioma cells with a CRISPR/Cas9-mediated knockout of the target antigen were resistant to CAR T cell-mediated cytotoxicity demonstrating their specificity. The in vivo activity of integrin-specific CAR T cells was tested in 2 orthotopic glioma models. Intratumoral treatment of glioma-bearing mice with αvβ5 or αvβ8 CAR T cells significantly prolonged their survival and cured a substantial fraction of these animals. CONCLUSION αvβ5- and αvβ8-specific CAR T cells exert strong and target-specific anti-glioma activity in vitro and prolong the survival of glioma-bearing mice. These data form the basis for a clinical evaluation of integrin-specific CAR T cells against glioblastoma.
CSIG-37. MERLIN S13 DEPHOSPHORYLATION DRIVES MENINGIOMA WNT SIGNALLING AND CELL PROLIFERATION
Authors: Charlotte Eaton, S John Liu, Calixto-Hope Lucas, Tim Casey-Clyde, Abrar Choudhury, Vikas Daggubati, Harish Vasudevan, Danielle Swaney, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract How Merlin-intact meningiomas arise in the absence of NF2/Merlin inactivation is incompletely understood. Here, we integrate single-cell RNA sequencing of 86,000 cells from meningioma xenografts with APEX2 proteomic proximity-labelling mass spectrometry and functional biochemical approaches to discover Merlin Serine 13 (S13) dephosphorylation drives meningioma Wnt signalling and cell proliferation. Cell biology, molecular biology, and biochemical techniques were used to validate Merlin functions in meningioma cells or xenografts using wildtype Merlin constructs or Merlin constructs encoding S13A, phosphomimetic S13D, or cancer-associated missense substitutions (L46R, A211D). Single-cell RNA sequencing of meningioma xenografts showed Merlin rescue activated the Wnt pathway in Merlin-deficient meningiomas. Proteomic proximity-labelling mass spectrometry revealed b-catenin, PKC, and PP1A interactions with wildtype Merlin, but not with Merlin L46R or A211D. b-catenin does not interact with other FERM family members, and Merlin contains a unique N-terminal domain (NTD) with a PKC phosphorylation motif overlapping with a PP1A dephosphorylation motif at S13. Thus, we hypothesized the Merlin S13, PKC, and PP1A may be important for Wnt signalling in Merlin-intact meningiomas. In support of this hypothesis, over-expression of wildtype Merlin or Merlin S13A but not Merlin DNTD, S13D, L46R, A211D, or other FERM family members drove meningioma Wnt signalling and sustained meningioma cell proliferation in vivo. Moreover, b-catenin was detected in proximity to Merlin S13D but not Merlin S13A in meningioma cells. Meningioma cell fractionation and immunofluorescence showed Merlin S13D over-expression stabilized b-catenin at the plasma membrane and inhibited Wnt signalling. Phospho-proteomic mass spectrometry and custom phospho-specific antibodies integrated with shRNA or siRNA gene suppression demonstrated PKC phosphorylated Merlin S13, but meningioma Wnt pathway activation induced PP1A to dephosphorylate Merlin S13 and drive cell proliferation. In summary, Merlin S13 dephosphorylation drives meningioma Wnt signalling and cell proliferation. These data reveal a novel tumor-promoting function of NF2/Merlin in Merlin-intact meningiomas.
CTNI-24. SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS
Authors: Chukwuyem Ekhator, Ramin Rak, Ramya Tadipatri, Ekokobe Fonkem, Jai Grewal
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE To report single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131]. BACKGROUND ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Design/ METHODS Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI]. RESULTS Three subjects were registered at our site onto ONC018 with age range 18–44yrs, 2/3 female, residing in Norway, India, and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: Glioblastoma (3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20 % decrease; MDASI:2/3 experienced decrease from baseline [median 6%], consistent with improved quality of life. No clinically significant laboratory abnormalities. All adverse events were grade I–II. CONCLUSIONS We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.
CTIM-07. PHASE II RANDOMIZED, BLINDED, PLACEBO-CONTROLLED TRIAL TESTING PP65 CMV MRNA DENDRITIC CELL VACCINE AND TETANUS-DIPHTHERIA TOXOID FOR NEWLY DIAGNOSED GBM (ATTAC II, NCT02465268)
Authors: Maryam Rahman, Ashley Ghiaseddin, Phuong Deleyrolle, Katherine B Peters, Gary Archer, John Sampson, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Immunotherapy is limited in efficacy for glioblastoma (GBM). The objective of this study was to evaluate the efficacy and immune effects of the pp65 mRNA dendritic cell (DC) vaccine with the use of lysosomal-associated membrane protein (LAMP) in two different formulations (full-length (fl) and short-length (sh). METHODS Patients who underwent resection of newly diagnosed GBM were enrolled and randomized to one of 3 arms: Arm 1) pp65-shLAMP mRNA DC with GM-CSF, Arm 2) pp65-flLAMP mRNA DC with GM-CSF, Arm 3) Unpulsed peripheral blood mononuclear cells (PBMC). After surgery, patients underwent leukapheresis for PBMC isolation and vaccines generation. Patients were treated with standard radiation and temozolomide followed by dose intensified adjuvant temozolomide at 75-100 mg/m2 x 21 days (aged less than 70) or standard dose at 150-200 mg/m2 x 5 days (patients 70 and older). Immunization started days 22-24 of cycle #1 with vaccines 1-3 delivered at 2 week intervals. All patients received tetanus-toxoid booster prior to vaccine 1. Patients continued to receive monthly vaccines for up to 10 vaccines with tetanus-diphtheria toxoid skin prep prior to vaccines 3, 6 and 9 (arms 1 and 2). Safety, efficacy and immune labs were evaluated. RESULTS Overall DC vaccines were well-tolerated with 2 SAEs possibly attributed to DC vaccination that met criteria as DLTs. Of recorded grade 2 or lower AEs, 2 were possibly attributable to DC vaccination. One patient was removed from the study due to failure to produce DC vaccines that met QA/QC release criteria. CONCLUSION In a large randomized and blinded patient cohort, delivery of CMV LAMP pp65 mRNA DC vaccines is feasible and safe in a multi-institutional setting. The primary endpoint of survival will be analyzed at the conclusion of the study.
INNV-23. MANAGING CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF CHRONIC GRAFT VERSUS HOST DISEASE FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION: A CASE REPORT
Authors: Ronak Kundalia, Anas Hanini, Tyra Gatewood, Asmita Mishra, Yolanda Pina, Sepideh Mokhtari
Journal: Neuro-Oncology (2022)

Abstract Central nervous system (CNS) manifestation of chronic graft versus host disease (cGVHD) is a rare, difficult to diagnose phenomenon that can follow allogeneic hematopoietic stem cell transplantation (HSCT). CNS-cGVHD typically onsets 2-31 months post-transplant, involves diffuse infiltration of inflammatory cells, demyelination, and cerebral vasculitis, and is associated with an extremely poor prognosis. We present a case of a 37-year-old man who developed seizures, myopathy, bilateral upper and lower extremity weakness, confusion, and irritability almost 2 years after HSCT for acute myeloid leukemia (AML). CNS-cGVHD diagnosis was confidently determined via magnetic resonance imaging (MRI) demonstrating enhanced focal white matter lesions, cerebrospinal fluid (CSF) studies demonstrating elevated globulin (12.7 mg/dL; normal range: 0-6 mg/dL) and elevated immunoglobulin G (IgG) synthesis rate (13.9 mg/d; normal range: ≤ 8 mg/d), and a right brain biopsy demonstrating encephalitis, perivascular inflammation, microglial activation, and gliosis with predominately intramural and perivascular CD3+ T-cells, CD4+ and CD8+ cells. Complete resolution of neurological symptoms, including seizures, was achieved with a combination of steroids, ibrutinib, intravenous immunoglobulin (IVIG), and anti-seizure medications. Improvements to CNS-cGVHD was further indicated by normalized MRI studies without abnormal enhancements and improved CSF studies with reduction in globulin levels (11.3 mg/dL) and complete normalization of IgG synthesis rate (≤ 0 mg/d). It is imperative that CNS-cGVHD be considered in patients that present with neurological signs post-transplant. An early, confident diagnosis generates prompt intervention and as demonstrated, can lead to complete resolution of neurological symptoms.
TMIC-46. DISRUPTING TRICELLULAR TIGHT JUNCTIONS TO ENHANCE BLOOD-BRAIN-BARRIER PERMEABILITY IN GLIOMA MODELS
Authors: Mahalia Dalmage, Nabanita Kundu, Minhye Kwak, Sanghee Lim, Christina Conrad, Sadhana Jackson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The blood-brain-barrier (BBB) is predominantly regulated by brain endothelial cells held together by junctional proteins. The BBB poses a significant hinderance to CNS drug entry of effective chemotherapy agents. Previous BBB studies have shown that disruption of tricellular and/or bicellular tight junctional proteins transiently increased CNS drug permeability. OBJECTIVE To evaluate the effect of drug proteins angubindin-1, C-CPE, and C-CPEmt on tight junction proteins angulin-1, claudin-3, and claudin 5, respectively, aimed at transiently enhancing BBB permeability and decreasing glioma growth. METHODS We evaluated junctional disruption with drug proteins, angubindin-1 (600µg/mL), C-CPE (200µg/mL), and C-CPEmt (200µg/mL) on rat brain endothelium. Endothelial junctional integrity studies were assessed by immunoblotting and cell-cell electrical impedance assays. Treatment effects on rat malignant glioma (S635) was measured via migration and rat glioma models. RESULTS Overall, we observed a time-dependent effect of drug proteins on junctional expression and function. Immunoblotting demonstrated a significant decrease (p&amp;lt; 0.05) in angulin-1 expression 5-hours after angubindin-1 treatment, while claudin-3 and claudin-5 expression barely decreased between 2 and 24-hours after C-CPE and C-CPEmt treatment, respectively. Cell-cell integrity was disrupted by 73%, 52%, and 69% compared with control, 3-hours after angubindin-1, C-CPE, and C-CPEmt treatment, respectively. Studies assessing qualitative junctional expression changes after drug proteins are ongoing. Gliomas cells expressed high angulin-1, and interestingly, migration was 50% decreased with angubindin-1 treatment, yet no migration changes were evident with C-CPE or C-CPEmt treatment. Rat glioma model studies evaluating liposomal doxorubicin combined with angubindin-1 are currently being explored to display effects on CNS drug concentrations, cytotoxicity, junctional expression, and survival. DISCUSSION Transient disruption of BBB tricellular junctions was seen with angubindin-1 treatment. Additionally, cell migration was hindered in angulin-1 overexpressing gliomas. These findings are promising and demonstrate the need for more combinational therapies aimed at increasing BBB permeability while also impairing glioma progression.
QLTI-06. CHARACTERISTICS OF TERMINATED GLIOBLASTOMA-RELATED CLINICAL TRIALS: A REVIEW OF THE CLINICALTRIALS.GOV DATABASE
Authors: Harshal Shah, Akash Mishra, Michael Gouzoulis, Netanel Ben-Shalom, Randy D'Amico
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma multiforme (GBM) is a devastating primary central nervous system tumor. Although past clinical trials have incrementally improved prognosis overall survival remains poor, emphasizing a need for further successful clinical trials. Terminated clinical trials are an inefficient use of financial, medical, and administrative resources and fruitlessly expose patients to the risks of experimental treatments. Therefore, premature trial terminations should be minimized whenever possible. GBM-related clinical trials in particular are known to suffer several inefficiencies in study design resulting in premature termination, and a 2019 Think Tank held by the Society of Neuro-Oncology intended to address this issue, suggesting optimizing participant accrual and efficacy assessments. The primary aims of the present study are to quantify terminated and completed GBM-related clinical trials and analyze reasons for premature trial termination. Using univariate and multivariate analysis we demonstrate factors associated with greater odds of trial termination. ClinicalTrials.gov, a clinical trial registry maintained by the National Library of Medicine, was queried to identify all completed and terminated GBM-related clinical trials. Trial characteristics pertaining to study design were abstracted from reported information on ClinicalTrials.gov for all trials, and the reason for trial termination was determined for those trials that were terminated early. Univariate analysis by Pearson’s chi-square and a multivariate logistic regression were performed to identify independent predictors of early trial termination. We identified 886 completed and terminated GBM-related trials between 2003 and 2020. Of these, 175 (19.8%) were terminated prior to completion. The most common reason for termination was participant accrual difficulties, accounting for 63 (36.0%) terminated trials. Trial termination was associated with trials that reported a primary purpose of diagnosis relative to treatment (OR = 2.952, p = 0.001). The identified predictors of trial termination should be considered when designing GBM-related clinical trials to minimize the odds of early trial termination.
CSIG-13. CLINICAL IMPACT OF CDKN2A/B DELETIONS IN IDH-MUTANT ASTROCYTOMAS
Authors: Alexander Yuile, Laveniya Satgunaseelan, Kimberley L Alexander, Subotheni Thavaneswaran, Michael Krasovitsky, Michael Buckland, Maggie Lee, Grace Wei, Marina Kastelan, Mark Wong, Isabella Wilson, Angela Bayly, Winny Varikat, Hao-Wen Sim, Ben Kong, Zarnie Lwin, Cassie Turner, Michael Back, Samuel Miller, Adrian Lee, Helen Wheeler
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND IDH-mutant astrocytomas with CDKN2A/B homozygous deletions (HD) are now categorized as grade 4 astrocytomas. It is unclear how these HD astrocytomas should be treated. We aimed to compare 3-year outcomes for HD versus heterozygous deleted (HeD) IDH-mutant astrocytomas, describe the prognostic impact of deletions relative to histologic grade and describe differences in outcomes based on treatment regimen. METHODS Molecular and clinical data concerning IDH-mutant glioma patients +/-CDKN2A/B deletions were retrieved across four neuro-oncology centers and two tumor banks from 01/2016-07/2021. RESULTS 48 patients with HD or HeD were identified. Median follow-up time was 4.0 years, median age 33 (range 20-74) years. Sixteen astrocytomas were histologic grade 4, remainder were grade 2 (n= 9) and grade 3 (n= 23). HD were detected in 16 patients. Survival data were unavailable in n= 1 HD and n= 2 HeD patients. 3-year OS for CDKN2A/B HD and HeD groups were 47% versus 67% (log-rank p= 0.004). For grades 2, 3 and 4, 3-year OS for HD were 100% (n= 1), 57% (n= 7) and 29% (n= 7) respectively, 3-year OS for HeD were 100% (n= 7), 56% (n= 16) and 57% (n= 7) respectively. In HD patients, six were treated with concurrent temozolomide-radiotherapy (3-year OS 50%) and five with radiotherapy and sequential temozolomide only (3-year OS 80%, log-rank p= 0.38). Treatment data were unavailable in two patients and three were treated with “other” regimens. Sequential regimens were preferentially used in histologic grade 2 and 3 cases. CONCLUSION Preliminary data are in keeping with current literature and are one of the first to describe outcomes based on clinical regimen. There was insufficient evidence of OS differences between concurrent and sequential therapy, though conclusions are limited by sample size and data maturity. Additional follow-up data are required to further define optimal treatment for these patients.